(1) Summary of the Invention
The present invention relates to the preparation of hydroxy substituted gamma butyrolactones. In particular, the present invention relates to a process for the preparation of isomers, in the (R) or (S) form. Further, the present invention relates to the preparation of 3 hydroxybutyrolactone and derivatives thereof such as 1,2,4-trihydroxybutane and 3,4-dihydroxybutyric acid-1-methyl ester from malic acid. Further still, the present invention relates particularly to the preparation of 4-hydroxy methyl butyrolactone from 4-hydroxybutane dicarboxylic acid dimethyl ester. The compounds as the isomers are particularly useful as intermediates for pharmaceuticals, agrochemicals favors and fragrances.
(2) Description of Related Art
U.S. Pat. Nos. 4,994.597 and 5,087,751 to Inone et al describe derivatives of 3,4-dihydroxybutyric acid. The pro ass for preparing the acid is different from the present invention involving a reaction of metal cyanide and a 3,4-dihydroxy butyl chloride and then hydrolyzing. The acid is an intermediate to 3-hydroxybutyrolactone.
(S)-3-Hydroxybutyrolactone is a key 4-carbon intermediate for the preparation of various drug intermediates including cholesterol lowering drugs. (S)-carnitine, and HIV protease inhibitor drugs, broad spectrum antibiotics.
(R)-3-Hydroxybutyrolactone or (R)-3,4-dihydroxybutyric acid gamma lactose is a key 4-carbon intermediate for the preparation of various drug intermediates. It can also be converted to 1-carnitine, a naturally occurring vitamin and ingredient used in several applications including treatment of various nervous system and metabolic disorders, as an additive in health foods and as a supplement in tonics. The world wide market for carnitine is estimated to be in the hundreds of metric tons. It is currently made by fermentation and by resolution of the d and 1 forms. There is no direct chemical route of any commercial value.
(S)-3-hydroxybutyrolactone can be prepared by the process of Hollingsworth (U.S. Pat. No. 5,374,773). (R)-3-Hydroxybutyrolactone cannot be prepared by the process since this would require the use of a starting material with a 4-linked L-hexane. No such material is known.
1-Malic acid (1-hydroxybutanedioic acid) is a 4-carbon dicarboxylic acid that la obtained in quantity, from apple juice and wine among other fruit juices. R can also be obtained by the hydraulics of fumaric acid and by the fermentation of sugars by some yeasts either as the free acid or as the polyester (polymalic acid). It is relatively inexpensive in isomeric forms.
There are rationally two major commercial routes to (S)-3-hydroxybutyrolactone involving enzymatic resolution. (1) One route to (S)-3-hydroxybutyrolactone involves the reduction of the dimethyl ester of malic acid to (S)-1,2,4-butanetriol, the preparation of a dioxolane intermediate to protect the 1 and 2 hydroxyl groups followed by oxidation of the 4-hydroxyl group to an aldehyde and then to an acid. The acid is then deprotected and the dihydroxy compound cyclized to (S)-3-hydroxybutyrolactone. This is shown by the following reaction (Scheme (I)). 
This is a very involved process and has no commercial value. It is complicated by the fan that the dioxolane is contaminated with about 10% of the dioxane. This is difficult to remove and results in the formation of contaminating 2-hydroxybutyrolactone. The process is described in Corey, et al., (E. J. Corey, H. Niwa and I. Knolle. xe2x80x9cTotal Synthesis of (S)-12-Hydroxy-5,8,14-cis-10-transeicosatetraenoic Acidxe2x80x9d. J. Amer. Chem Soc. 100 1942-1943(1978)).
(2) Another route involves a process for the direct reduction of malic acid to (S)-3-hydroxybutyric acid and the transformation to (S)-3-hydroxybutyrolactone. This reaction employs the dimethyl sulfide complex of borane and a catalytic amount of sodium borohydride as the reducing system Borane dimethyl sulfide requires specialized equipment to handle and an oxygen free and moisture free environment. It is very toxic and dimethyl sulfide is a very noxious gas. The reducing system is very expensive. The process is described in Saito et al., (S. Saito, T. Hasegawa, M. Inaba, R. Nishida, T. Fujii, S. Nomizu, and T. Moriwaki. xe2x80x9cCombination of borane-dimethyl sulfide complex with catalytic sodium tetrahydroborate as a selective reducing agent of a-hydroxy esters, versatile chiral building block from (S)-(xe2x88x92)-malic acidxe2x80x9d Chem Letts. 1389-1392 (1984)).
Other references which are pertinent to the present invention are: Arth et al., Liebigs Ann. 2037-2042 (1995) who describe the production of 1,2,4-butanetriol from malic acid using a borane reduction. Tandon, V., et al., J. Org. Chem. 48:767-2769 (1983) who describe the cyclization of 1.2.4-triol to tetrahydrofuran. Boger a al., 46 1208-1210 (1981) who describe a process for producing chiral derivatives from malic acid. Herradon, Asymmetry 2 191-194 (1991) who describes the use of a borane-dimethyl sulfide complex reduction to 1,2,4 butanetriol. This is a difficult process to practice because of problems in handling the butane, Hanessian et al., 199 2146-2147 (1984) describe triol derivatives produced from malic acid using boranes.
The use of alkali metal borohydrides, particularly lithium borohydride, as a reducing and hydrogenerating agent are generally known in the prior art. They are described in U.S. Pat No. 2,683,721 to Schlesinger et al. These are not known for use in preparing hydroxy substituted gamma butyrolactones.
The preparation of la lactones in general is described for instance in Advanced Organic Chemistry 1977, page 363. U.S. Pat. Nos. 3,024,250 to Klein et al., 3,868,370 to Smith, 3,997,569 to Powell, 4,105,674 to De Thomas et al., 4,155,919 to Ratatouille et al., 4,772.729 to Rao, 4,940,805 to Fisher et al., 5,292,939 to Hollingsworth, 5,319,110 to Hollingsworth, 5,374,773 to Hollingsworth, and 5,502,217 to Fuchikami et al. These patents describe diverse processes for the preparation of lactones. They particularly do not describe the use of malic acid as a starting material. The processes described are also relatively complex.
There is a need for an improved process for the preparation of hydroxy butyrolactones and related alcohols and acid derivatives, particularly 4-hydroxy methyl butyrolactone, 3-hydroxybutyrolactone, 1,2,4-butanetriol and 3,4-dihydroxy acid, methyl ester in high yield.